Nanostructured lipid carriers for topical drug delivery: A comprehensive review of design, mechanisms, and therapeutic advances

Nanostructured Lipid Carriers (NLCs) represent a significant advancement in topical drug delivery, overcoming key limitations of earlier lipid-based systems such as Solid Lipid Nanoparticles (SLNs). By combining solid and liquid lipids into a nanometric matrix, NLCs enhance drug entrapment, increase loading capacity, and provide greater stability. These properties support improved skin permeation, controlled release, and targeted delivery to deeper skin layers, thereby minimizing systemic side effects. This review critically examines the scientific foundation and formulation strategies of NLCs, including their composition, classification, and manufacturing methods. It highlights the influence of lipid and surfactant selection on physicochemical parameters such as particle size, zeta potential, and entrapment efficiency. Detailed mechanisms of drug release and skin penetration through intercellular, transcellular, and trans-appendageal pathways are explored, alongside the role of NLCs in forming occlusive films that enhance skin hydration and barrier repair. The review also evaluates the therapeutic efficacy of NLCs in treating inflammatory disorders, fungal infections, and chronic dermatological conditions based on preclinical and clinical studies. NLCs offer promising advantages in topical therapy, including superior bioavailability, sustained drug retention, and enhanced patient compliance. Their integration with precision medicine and cosmetic dermatology marks them as next-generation carriers for safe and effective topical drug delivery. • NLCs redefine topical nanomedicine with superior bioavailability. • Solid–liquid lipid design enables high drug loading and stability. • Enhanced penetration routes improve dermal targeting and efficacy. • Hybrid and stimuli-responsive NLCs advance precision nanotherapy. • Translational gaps include scale-up, safety, and regulatory clarity.